1. Field of the Invention
The present invention relates to a method of preparing a mixed formulation of sustained release microspheres with different compositions by a continuous one-step process.
2. Description of the Prior Art
Sustained release of drugs at constant rates is conventionally achieved by preparing microspheres with a single composition using a single mixture of a biodegradable polymer, a drug, an additive, a solvent, and the like, by a spray-drying method or other methods. From the sustained release microspheres, the release of a drug must be properly controlled at the initial phase and for a continuous period to obtain optimal pharmaceutical efficacy for a predetermined period of time. To date, the initial release and continuous release of a drug have been controlled by employing microspheres prepared by varying the following parameters: type and concentration of the biodegradable polymer, content of the drug, amount of the additive for control of the release rate of the drug, solvent type, and the like. Other parameters also can control the drug release by changing several physical properties of the microspheres, which include, in case of using a spray-drying method, solution spraying method, spray nozzle type, feeding rate of a solution to be sprayed, amount of air supplied to a spray nozzle for an air-assisted atomization, frequency of ultrasonic wave for an ultrasonic atomization, supplied amount of drying air, supply rate and temperature of the drying air and the like.
Of the above parameters, the biodegradable polymer type is the most important factor determining the release rate of drugs from microspheres. Among several biodegradable polymers used in the preparation of sustained release microspheres, the most widely used one is poly(lactide-co-glycolide) (PLGA) (DeLuca, P. P. et al., Biodegradable polyesters for drug and polypeptide delivery, in: El-Nokaly, M. A., Piatt, D. M., and Charpentier, B. A. (Eds.), Polymeric delivery systems, properties and applications, American Chemical Society, pp. 53-79 (1993); Park, T. G., Biomaterials, 16, 1123-1130 (1995); Anderson, J. M. and Shive, M. S., Adv. Drug. Del. Rev., 28, 5-24 (1997); Tracy, M. A. et al., Biomaterials, 20, 1057-1062 (1999)). PLGA has characteristic physicochemical features in that, for example, its biodegradation rate varies according to the ratio of lactic acid residues to glycolic acid residues, and their molecular weights and hydrophilicity, and, thus, PLGA is a major factor to determine durations of drug release. Therefore, when a drug delivery system for sustained release of a drug for a predetermined period is prepared, one must first select a polymer being properly biodegraded for the predetermined period. In particular, when drug release is desired to be maintained for a period longer than one month, sustained release microspheres are prepared by employing PLGA copolymers with higher lactic acid content, higher molecular weights, or lower hydrophilicity. However, there is a significant problem with the sustained release microspheres prepared using only a single polymer selected as described above, as follows. Since the polymer is degraded at very slow rates, a drug encapsulated in the microspheres is often not released at the initial phase. Also, this problem cannot be overcome by varying the aforementioned parameters, thereby making it difficult to obtain desired release patterns of drugs for a desired long period.
On the other hand, many recent studies are associated with an alternative method of preparing microspheres for sustained release of drugs, which includes mixing two or more polymers with different degradation rates at a predetermined ratio to control both initial release and continuous release of the drugs from the microspheres (Ravivarapu, H. B., Burton, K., DeLuca, P. P., Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres, Eur J Pharm Biopharm, 50(2), 263-70, 2000). However, the microsphere formulation comprising a blend made from two or more different polymers with a single composition is also problematic in that, in a single microsphere, a rapidly degraded polymer affects the degradation rate of other polymers having relatively slow degradation rates, resulting in an increase in degradation of the microsphere. Thus, the microsphere formulation prepared by combining two or more polymers at a single (fixed) ratio is not effective in achieving both desired initial release and continuous release of drugs for a long period.
The disadvantage of the single-composition microsphere formulation can be overcome by separately preparing two or more microsphere formulations using two or more different polymers and combining the microsphere formulations at a proper ratio to give a microsphere formulation allowing for sustained release of drugs for a desired period (U.S. Pat. No. 4,897,268, Burton, K. W., Shameem, M., Thanoo, B. C., DeLuca, P. P., Extended release peptide delivery systems through the use of PLGA microsphere combinations, J Biomater Sci Polym Ed. 11(7), 715-29, 2000, Ravivarapu, H. B., Burton, K., DeLuca, P. P., Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres, Eur J Pharm Biopharm, 50(2), 263-70, 2000). However, this microencapsulation is a complicated and uneconomical process because two or more kinds of microspheres should be individually prepared to achieve desired drug release patterns.
Therefore, with respect to the preparation of sustained release microspheres encapsulating drugs, there is a need for a simple and economical method that is capable of achieving a desired release of drugs regardless of a desired period.